Summary of work: Beta cells of the pancreas, which make insulin, do not respond normally to glucose in type 2 diabetes. In conjunction with this, and despite all treatments currently available to treat diabetes beta cell function continues to deteriorate over time. We have been working for some time with GLP-1, a naturally occurring peptide, produced and released from the gut in response to food. It augments the insulin-releasing capacity of beta cells in response to food. Of great interest is the finding that in type 2 diabetes pharmacological doses of GLP-1 can normalize blood sugars, ie, euglycemia is achieved. However, GLP-1 has a biological half-life of only 4-6 minutes and has to be given systemically. This means that it would have to be given continuously in order to maintain euglycemia. The Hela monster is a lizard which lives in Arizona. It produces in its venom a homolog of GLP-1 which is called Exendin-4. When it is given systemically to rodents its biological half-life is 12-16 hours. We gave Exendin-4 intraperitoneally, once daily, to db/db mice. Db/db mice develop obesity and a type of diabetes resembling type 2 diabetes of humans. Within 4 days of giving Exendin-4 blood sugars were normalized in the diabetic animals. We continued the injections for a further 10 weeks. Blood sugars showed a rise over time in the diabetic animals treated with Exendin-4 but they remained at least half the level of the non-treated animals. Hemoglobin A1c, a marker of long-term control of blood sugars, was 5.7% in the treated animals and 9.1% in the non-treated animals. We are expanding on this project to find the minimal amount of Exendin-4 that is anti-diabetogenic and we are looking at the mechanisms whereby Exendin-4 has such beneficial long-term effects.